中文摘要：研究分析了一种新的抗HIV-1的mRNA 治疗疫苗的效力。该疫苗由活化信号（TriMix: CD40L+CD70+caTLR4）与抗原序列结合而成，抗原序列包含16个源于Gag、Pol、Vif和Nef的片段。研究结果表明：对编码HTI+TriMix 的HIV-感染组未成熟单核细胞进行电穿孔能够激活树突状细胞，从而上调成熟标记、细胞因子产量和T细胞反应，这一现象通过炎症反应增强、细胞因子分泌增多得到了验证。研究证实，上调编码强激活信号和HIV抗原的mRNA水平能够刺激T细胞去干扰树突状细胞，能够提高该疫苗刺激产生抗原特异性免疫的能力。这些研究为基于抗原编码RNA的治疗性 HIV疫苗的研制提供了重要基础。
外文摘要：Background: The development of a prophylactic vaccine against HIV-1 has so far not been successful. Therefore, attention has shifted more and more toward the development of novel therapeutic vaccines. Here, we evaluated a new mRNA-based therapeutic vaccine against HIV-1-encoding activation signals (TriMix: CD40L+CD70+caTLR4) combined with rationally selected antigenic sequences [HIVACAT T-cell immunogen (HTI)] sequence: comprises 16 joined fragments from Gag, Pol, Vif, and Nef). Methods: For this purpose, peripheral blood mononuclear cells from HIV-1-infected individuals on cART, lymph node explants from noninfected humans, and splenocytes from immunized mice were collected and several immune functions were measured. Results: Electroporation of immature monocyte-derived dendritic cells from HIV-infected patients with mRNA encoding HTI+TriMix potently activated dendritic cells which resulted in upregulation of maturation markers and cytokine production and T-cell stimulation, as evidenced by enhanced proliferation and cytokine secretion (IFN-gamma). Responses were HIV specific and were predominantly targeted against the sequences included in HTI. These findings were confirmed in human lymph node explants exposed to HTI+TriMix mRNA. Intranodal immunizations with HTI mRNA in a mouse model increased antigen-specific cytotoxic T-lymphocyte responses. The addition of TriMix further enhanced cytotoxic responses. Conclusion: Our results suggest that uptake of mRNA, encoding strong activation signals and a potent HIV antigen, confers a T-cell stimulatory capacity to dendritic cells and enhances their ability to stimulate antigen-specific immunity. These findings may pave the way for therapeutic HIV vaccine strategies based on antigen-encoding RNA to specifically target antigen-presenting cells.
外文关键词： HIV vaccines；HTI；mRNA electroporation
作者：Guardo, AC; Joe, PT; Miralles, L; Bargallo, ME; Mothe, B; Krasniqi, A; Heirman, C; Garcia, F; Thielemans, K; Brander, C; Aerts, JL; Plana, M
作者单位：巴塞隆纳医院
期刊名称： AIDS
期刊影响因子：4.407
出版年份：2017
出版刊次：1
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